Belinostat and Azacitidine in Treating Patients With Advanced Hematologic Cancers or Other Diseases

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose of PXD101 (belinostat) when given in combination with azacitidine (when azacitidine is utilized at a dose range where its effects on cellular differentiation are known to be predominant) in patients with advanced hematologic cancers or other diseases.

SECONDARY OBJECTIVES:

I. Identify any additive or synergistic effects of this regimen on pharmacodynamic parameters, including apoptosis and re-expression of specific target genes.

II. Assess any evidence of clinical activity (complete remission, partial remission, hematologic improvement, stable disease) of this regimen in these patients.

OUTLINE: This is a dose-escalation study of belinostat followed by a randomized study.

Patients receive azacitidine subcutaneously (SC) and belinostat intravenously (IV) over 30 minutes on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of belinostat until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. After the MTD is determined, additional patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (with trilineage dysplasia or arising from MDS) are randomized to 1 of 2 treatment arms.

Arm I: Patients receive azacitidine SC on days 1-5.

Arm II: Patients receive azacitidine as in arm I and belinostat at the MTD IV over 30 minutes on days 1-5.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After receiving one course, patients randomized to arm I may crossover to receive treatment on arm II.

For patients enrolled in the randomized portion of the study, bone marrow aspirates are obtained at baseline, and after course 1 for correlative studies. Samples are examined by gene expression analysis of p15 and p21, DNA methylation of p15INK4B, and apoptosis by RT-PCR and flow cytometry. Pharmacodynamic assays are also performed.

After completion of study treatment, patients are followed periodically for up to 2 years.

Inclusion criteria

• Histologically confirmed diagnosis of 1 of the following:

• Relapsed or refractory acute myeloid leukemia (AML)
• Relapsed or refractory acute promyelocytic leukemia (must have failed both tretinoin and arsenic trioxide)
• Relapsed or refractory acute lymphoblastic leukemia
• Secondary AML, including AML arising from antecedent hematologic diseases, such as myelodysplastic syndromes (MDS) or myeloproliferative disorders, OR therapy-related AML
• Chronic myelogenous leukemia in accelerated or blast phase
• Advanced phases of Philadelphia chromosome-negative (Ph-) chronic myeloproliferative disorders, as defined by ≥ 1 of the following:

• Presence of anemia (hemoglobin < 10 g/dL and/or red blood cell transfusion dependent)
• Presence of palpable splenomegaly
• MDS, including chronic myelomonocytic leukemia

• Must have intermediate or high-risk International Prognostic Scoring System (IPSS) scores (≥ 0.5)
• Low-risk IPSS scores allowed provided ≥ 1 of the following criteria are met:

• Hemoglobin < 10 g/dL and/or red blood cell transfusion dependent
• Platelet count < 50,000/mm³
• Absolute neutrophil count < 1,000/mm³
• Refractory disease OR no standard therapy exists
• Evidence of AML associated with dysplasia on bone marrow histology for elderly patients (i.e., > 60 years old) who are previously untreated and not candidates for or unwilling to undergoing induction therapy
• No known active CNS involvement with disease
• CALGB performance status (PS) 0-2 OR Karnofsky PS 60-100%
• Bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's syndrome)
• ALT ≤ 3 times upper limit of normal (unless due to disease)
• Creatinine ≤ 2 mg/dL
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to PXD101 or Azacitidine
• No history of allergic reactions to mannitol
• No history of dose-limiting toxicity during prior treatment with Azacitidine
• No concurrent uncontrolled illness including, but not limited to, the following:

• Ongoing or active infection
• Symptomatic congestive heart failure
• Unstable angina pectoris
• Cardiac arrhythmia
• Psychiatric illness or social situation that would preclude compliance with study requirements
• No marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 500 msec)
• No long QT syndrome
• No uncontrolled cardiovascular disease, including the following:

• Severe uncontrolled hypertension
• Uncontrolled congestive heart failure related to primary cardiac disease
• Uncontrolled cardiac arrhythmia
• Uncontrolled ischemic or severe valvular heart disease
• Myocardial infarction within the past 6 months
• See Disease Characteristics
• Recovered from prior therapy
• At least 2 weeks since prior chemotherapy (6 weeks for mitomycin C or nitrosoureas)
• At least 2 weeks since prior radiotherapy
• At least 4 weeks since prior investigational agents
• At least 24 hours since prior hydroxyurea
• At least 2 weeks since prior valproic acid
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents
• No concurrent medication that may cause torsade de pointes
• No other concurrent anticancer therapy, including chemotherapy, radiotherapy, or biological agents